The manipulation of replication characteristics and differentiated state of cells is an area of great interest for the development of cancer therapies, the field of tissue/organ transplantation and in the field of aging generally.
Normal cells typically divide for a highly restricted number of generations, and then enter a state of replicative senescence that can be characterized by acidic β-galactosidase staining, and in the case of many human cells, shortened telomeres leading to DNA damage checkpoint arrest. For example, normal human fibroblasts rarely if ever spontaneously immortalize in vitro. Senescent human fibroblasts have been demonstrated to have the capacity to both stimulate the proliferation of premalignant and malignant epithelial cells in culture, and to increase the tumorigenicity of premalignant epithelial cells in mouse xenografts. Thus, senescent human fibroblasts can create a tissue microenvironment that promotes multiple stages of tumor evolution through the senescence-associated secretory phenotype (SASP). This phenotype develops slowly and only after DNA damage, when senescent fibroblasts begin secreting IL-6, IL-8 and other cytokines that promote transformation of epithelial cells. In addition, said SASP is believed to play an important role in the aging of tissues by promoting the destruction of extracellular matrix, and triggering other age-related pathologies.
Similarly, normal cultured somatic cell types such as cultured human somatic cell types rarely if ever spontaneously transform to malignant cells capable of forming malignant tumors. Such transformation of normal somatic cells into malignant cells capable of forming malignant tumors generally requires the exogenous introduction of oncogenes, the abrogation of tumor suppressor genes, and the exogenous introduction of the catalytic component of telomerase.
In addition, normal cultured mammalian cells, such as those from humans rarely if ever spontaneously revert back to a state of pluripotency. This lack of competence for reprogramming leads to inefficiencies in transcriptional reprogramming by the exogenous addition of factors such as OCT4, SOX2, MYC, LIN28, KLF4, and NANOG.
There remains a need in the art for effective compositions and mechanisms that enable control of telomerase activity, the conversion of a normal cell to its malignant counterpart, and reprogramming of a normal cell to pluripotency to permit therapeutic treatment of diseases and conditions related to cell aging, screening and targets for the diagnosis and therapy for cancer, and to facilitate the reprogramming of somatic cells to pluripotency.